Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that afflicts approximately 400,000 people in the United States alone. An ideal anti-inflammatory therapy for MS should be one that is neural antigen-specific, i.e., it suppresses only inflammatory cells that cause neural tissue injury but not those that protect against infections. Recently, major advances have been made in our understanding of a naturally occurring lymphocyte subset called regulatory T (Treg) cells that are used precisely by the immune system to perform antigen-specific immunosuppression. They play indispensable roles in maintaining health since their deficiency in mice and humans causes fatal inflammatory diseases. They may also be directly involved in the pathogenesis of MS since their functions and numbers are significantly reduced in patients studied by several groups. More importantly, a number of laboratories including ours have shown that adoptive transfer of myelin-specific Treg cells effectively prevents and ameliorates experimental autoimmune encephalomyelitis, a model for MS, in a myelin-specific manner, not affecting immunity against unrelated antigens. These new advances have led to the recognition that transfusion of myelin-specific Treg cells represents an ideal form of adoptive cell therapy for MS. However, Treg cells are still among the least understood T cell subsets, and consequently the most difficult to use for therapeutic applications. This proposal is inspired by recent discoveries from several laboratories including ours that c-Rel, the lymphoid member of the nuclear factor-?B family and a risk factor for human inflammatory diseases, is a key controller of Treg cell development and function. The objectives of this proposal are to (i) determine how c-Rel turns on Foxp3 gene to initiate Treg cell differentiation, (ii) determine how Foxp3 terminates c-Rel activity to stabilize Treg cell function and (iii) develop a new combination therapy for autoimmune encephalomyelitis by targeting the c-Rel-Foxp3 axis.